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Coronary artery calcification is related to functional polymorphism of matrix metalloproteinase 3: the Helsinki
Perttu J Pöllänen1, Terho Lehtimäki, Erkki Ilveskoski
1Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, FinnMedi 2 3rd fl., PO Box 2000, FIN-33521, Tampere, Finland.
Abstract:
Matrix metalloproteinase 3 (MMP3) is expressed in human coronary atherosclerotic lesions and is known to be involved in degradation of the plaque and to be co-localized with calcium and fibrin deposits in advanced lesions, indicating a possible role of MMP3 in arterial calcification. The MMP3 gene promoter polymorphism leads to low promoter activity 6A6A, intermediate promoter activity 5A6A and high promoter activity 5A5A genotypes. To determine whether these genotypes predict the extent of atherosclerosis we investigated their association with different types of coronary lesions in an autopsy series of 300 middle-aged white Finnish men (aged 35-69 years) from the Helsinki Sudden Death Study (HSDS). Areas of the coronary wall covered with different atherosclerotic lesions were measured and MMP3 genotypes were determined by PCR and minisequencing. In men >/=53 years the mean area of calcified lesion in the most severely affected coronary artery was significantly associated with the MMP3 genotype (P=0.029). Subjects with high promoter activity genotypes had on average larger calcified lesion areas than those with the low-activity genotype. The MMP3 genotype (P=0.025) persisted as an independent predictor of mean calcified lesion area after stepwise adjustment for age, BMI, hypertension, diabetes, number of affected vessels and smoking. These data provide evidence that the proposed effect of MMP3 in the process of atherogenesis may be modified by the MMP3 genotype.
Insights
Matrix metalloproteinase 3 (MMP3) gene variants influence arterial calcification in men. Higher MMP3 promoter activity correlated with larger calcified lesion areas, suggesting a genetic role in atherosclerosis progression.
Area of Science:
- Cardiovascular Research
- Genetics
- Atherosclerosis
Background:
- Matrix metalloproteinase 3 (MMP3) is implicated in atherosclerotic plaque degradation and arterial calcification.
- MMP3 is co-localized with calcium and fibrin in advanced coronary lesions.
- MMP3 gene promoter polymorphisms (e.g., 5A5A, 5A6A, 6A6A) affect gene activity.
Purpose of the Study:
- To investigate the association between MMP3 genotypes and the extent of coronary atherosclerosis.
- To determine if MMP3 genotypes predict calcified lesion areas in middle-aged men.
Main Methods:
- Autopsy series of 300 middle-aged white Finnish men (Helsinki Sudden Death Study).
- Measurement of coronary atherosclerotic lesion areas.
- Determination of MMP3 genotypes using PCR and minisequencing.
Main Results:
- In men aged 53 years and older, MMP3 genotype significantly associated with mean calcified lesion area (P=0.029).
- Individuals with high promoter activity genotypes (e.g., 5A5A) had larger calcified lesion areas compared to low-activity genotypes (e.g., 6A6A).
- MMP3 genotype remained an independent predictor of calcified lesion area after adjusting for cardiovascular risk factors.
Conclusions:
- MMP3 genotype influences the extent of arterial calcification in men.
- The MMP3 genotype modifies the proposed role of MMP3 in atherogenesis.
- Genetic variations in MMP3 may play a role in the development and progression of coronary atherosclerosis.
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